Restenosis is the closure of a peripheral or coronary artery following trauma to the artery. Restenosis is believed to be a natural healing reaction to the injury of the arterial wall that is caused by angioplasty procedures. The healing reaction begins with the clotting of blood at the site of the injury. The final result of the complex steps of the healing process is intimal hyperplasia, the migration and proliferation of smooth muscle cells, until the artery is again stenotic or occluded. Restenosis is most often caused by efforts to open an occluded portion of an artery, such as, for example by dilation, ablation, atherectomy or laser treatment. For angioplasty procedures, restenosis occurs at a rate of about 20-50% depending on the vessel location, lesion length, severity of injury, individual propensities to wound healing, the elastic character of a particular vessel, and the like.
Intravascular stents have been disclosed to prevent restenosis. Intravascular stents are medical implants, typically in the form of a hollow cylinder, that are positioned against a body lumen. Metallic intravascular stents are generally permanently implanted in coronary or peripheral vessels. Metal stent designs include those of U.S. Pat. No. 4,733,665 to Palmaz, U.S. Pat. No. 4,800,882 to Gianturco or U.S. Pat. No. 4,886,062 issued to Wiktor. Polymeric stents are also known and both metal and polymeric stents include self-expanding types of stents or balloon-expandable stents. The stent is typically inserted by catheter into a vascular lumen and expanded into contact with the diseased portion of the arterial wall to position the stent and provide internal support for the lumen. Even with the stent in place, restenosis can occur and the stent itself can cause undesirable local thrombosis.
To alleviate the problems associated with stents, anticoagulant substances such as heparin and thrombolytic agents have been incorporated into the stent. These patents include, for example, U.S. Pat. Nos. 5,419,760; 5,342,621; 5,380,299; 5,429,634; 5,304,121; and 5,383,928. Stents have also been prepared from bio-compatible materials including biostable or bioabsorbable polymers. U.S. Pat. No. 5,510,077 discloses an intraluminal stent comprising fibrin.
Stents have been used as delivery vehicles for drugs. The stent delivers drug at the site of contact with the vasculature. Local delivery is advantageous in that the effective local concentration of delivered drug is much higher than can normally be achieved by systemic administration. The use of stents for drug delivery is discussed in U.S. Pat. No. 5,102,417 to Palmaz and in international patent applications WO 91/12779 and WO 90/13332. These applications suggest that antiplatelet agents, anticoagulant agents, antimicrobial agents, antimetabolic agents and other drugs could be supplied by stent to reduce the incidence of restenosis. U.S. Pat. No. 5,464,650 discloses the application of solvent with a drug and a polymer to the body of a stent to deliver drugs to a vessel wall. Drug delivery is necessary for the treatment of some diseases; however, a concern related to the use of stents for drug delivery is that drug delivery may not be sustainable from a stent. Over time the drug concentration on the stent may be diluted out, through drug inactivation, degradation, dilution into the adjacent lumen or reduced through delivery to the surrounding tissues.
Stents seeded with endothelial cells (Dichek, et al. Circulation 80:1347-1353, 1989) are disclosed as a method for delivering recombinant protein over time to the vascular wall. This method requires autologous cells. The endothelial cells need to sustain delivery of the protein at concentrations that will be therapeutically effective to the cells of the lumen wall. The excreted protein concentration produced by the endothelial cells that is required to treat the surrounding vascular tissue can be quite high. Moreover, the endothelial cells are likely to die out in the absence of surrounding supportive tissue. Improved methods for the sustainable delivery of therapeutic protein(s) and nucleic acid are needed.
Viruses are useful vehicles for gene delivery. A variety of genetically modified viruses are known in the art. For example, there are a variety of RNA and DNA based viruses that are useful for gene delivery. Adenoviruses are particularly useful as gene delivery vehicles. The virus particle is relatively stable and the adenovirus genome does not undergo rearrangement at a high rate.
Catheters have been used to deliver liposomes and viruses to the vascular wall. Chang, et al (Science 267:518-522, 1995) disclose the use of a catheter to deliver an adenoviral vector encoding the retinoblastoma gene product to an injured vessel wall. International patent application WO 95/25807 to Nabel et al. and Ohno et al. (Science 265:781-784, 1994) discloses the delivery of an adenoviral vector to blood vessel cells using an angioplasty balloon catheter.
The duration of exposure to gene transfer reagents to the vascular wall is likely to be an important variable in the effectiveness of gene delivery to cells lining lumen walls. Lumens that support rapid unidirectional fluid flow (i.e., in one example, the coronary arteries) cannot be occluded, yet these tissues need sustained exposure to gene transfer reagents for effective nucleic acid delivery. Ohno et al. (supra) used a balloon angioplasty catheter to administer virus to a blood vessel lumen of the leg. The balloon catheter was positioned in the vessel, occluding blood flow for twenty minutes. Balloon catheters generally block fluid flow and cannot be held in place for prolonged periods to facilitate gene transfer. Balloon catheters cannot be used for gene therapy in coronary arteries or other tissues facilitating rapid fluid flow. Even in areas where there is not heavy unidirectional fluid flow, it is unlikely that catheters can be held in place in vivo for extended periods to facilitate gene transfer without patient discomfort or without surgical procedures that require general anesthesia. These problems have been recognized in the art, as disclosed by Barinaga (Science 265:738, 1994).
A device that directly contacts the injured or damaged tissue in need of gene transfer therapy for extended periods of time is needed, but these devices should not interfere with lumen function. Contact of a bare device, such as a catheter loaded with virus, may not provide the long term contact necessary to maximize gene transfer. Moreover, virus is washed from the catheters as they move through the vasculature to the site of vessel injury and this diluting effect reduces the efficiency of gene transfer from these devices. Free unassociated virus can also pose a risk for widespread uncontrolled gene delivery.